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Phosphodiesterase 3/4 Inhibitor Zardaverine Exhibits Potent and Selective Antitumor Activity Against Hepatocellular Carcinoma Both in Vitro and in Vivo Independently of Phosphodiesterase Inhibition

Phosphodiesterase 3/4 Inhibitor Zardaverine Exhibits Potent and Selective Antitumor Activity Against Hepatocellular Carcinoma Both in Vitro and in Vivo Independently of Phosphodiesterase Inhibition

Liping Sun, Haitian Quan, Chengying Xie, Lei Wang, Youhong Hu, Liguang Lou

PLoS One. 2014 Mar 5;9(3):e90627.

PMID: 24598942

Abstract:

Hepatocellular carcinoma (HCC) is the fifth common malignancy worldwide and the third leading cause of cancer-related death. Targeted therapies for HCC are being extensively developed with the limited success of sorafinib. In the present study, we investigated the potential antitumor activity of zardaverine, a dual-selective phosphodiesterase (PDE) 3/4 inhibitor in HCC cells both in vitro and in vivo. Although all zardaverine, PDE3 inhibitor trequinsin and PDE4 inhibitor rolipram increased intracellular cAMP levels through inhibiting PDE activity, only zardaverine significantly and selectively inhibited the proliferation of certain HCC cells, indicating that the antitumor activity of zardaverine is independent of PDE3/4 inhibition and intracellular cAMP levels. Further studies demonstrated that zardaverine induced G0/G1 phase cell cycle arrest of sensitive HCC cells through dysregulating cell cycle-associated proteins, including Cdk4, Cdk6, Cdk2, Cyclin A, Cyclin E, p21 and Rb. Notably, Rb expression was reversely related to the cell sensitivity to zardaverine. The present findings indicate that zardaverine may have potential as targeted therapies for some HCC, and the likely mechanism of action underlying its selective antitumor activity may be related to its regulation of Rb or Rb-associated signaling in cell cycles.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP101975104	Zardaverine		101975-10-4	Price

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